6-109732621-GTTT-GTT

Variant names:

• chr6-109732621-GT-G
• rs11377100
• NM_014845.6:c.447-3delT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_014845.6(FIG4):​c.447-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000088 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0043 (0 hom.)
• Consequence: FIG4 NM_014845.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0950
• Publications: 4 publications found

Genes affected

FIG4 (HGNC:16873): (FIG4 phosphoinositide 5-phosphatase) The protein encoded by this gene belongs to the SAC domain-containing protein gene family. The SAC domain, approximately 400 amino acids in length and consisting of seven conserved motifs, has been shown to possess phosphoinositide phosphatase activity. The yeast homolog, Sac1p, is involved in the regulation of various phosphoinositides, and affects diverse cellular functions such as actin cytoskeleton organization, Golgi function, and maintenance of vacuole morphology. Membrane-bound phosphoinositides function as signaling molecules and play a key role in vesicle trafficking in eukaryotic cells. Mutations in this gene have been associated with Charcot-Marie-Tooth disease, type 4J. [provided by RefSeq, Jul 2008]

FIG4 Gene-Disease associations (from GenCC):

• Charcot-Marie-Tooth disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• Charcot-Marie-Tooth disease type 4J

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine
• Yunis-Varon syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• amyotrophic lateral sclerosis type 11

  Inheritance: Unknown, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp
• amyotrophic lateral sclerosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• bilateral parasagittal parieto-occipital polymicrogyria

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 6-109732621-GT-G is Benign according to our data. Variant chr6-109732621-GT-G is described in ClinVar as Benign. ClinVar VariationId is 1610293.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FIG4	NM_014845.6	c.447-3delT		splice_region_variant, intron_variant	Intron 4 of 22	ENST00000230124.8	NP_055660.1
FIG4	XM_011536281.4	c.384-3delT		splice_region_variant, intron_variant	Intron 4 of 22		XP_011534583.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FIG4	ENST00000230124.8	c.447-15delT		intron_variant	Intron 4 of 22	1	NM_014845.6	ENSP00000230124.4

Frequencies

GnomAD3 genomes AF: 0.0000882 AC: 13 AN: 147342 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000124

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000677

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000212

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000898

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00354 AC: 581 AN: 164298 AF XY: 0.00341

Gnomad AFR exome AF: 0.000200

Gnomad AMR exome AF: 0.00543

Gnomad ASJ exome AF: 0.00170

Gnomad EAS exome AF: 0.00359

Gnomad FIN exome AF: 0.00272

Gnomad NFE exome AF: 0.00354

Gnomad OTH exome AF: 0.00404

GnomAD4 exome AF: 0.00428 AC: 3688 AN: 860780 Hom.: 0 Cov.: 17 AF XY: 0.00410 AC XY: 1832 AN XY: 447000

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00157 AC: 31 AN: 19808

American (AMR) AF: 0.00435 AC: 164 AN: 37724

Ashkenazi Jewish (ASJ) AF: 0.00176 AC: 36 AN: 20460

East Asian (EAS) AF: 0.00173 AC: 58 AN: 33486

South Asian (SAS) AF: 0.00387 AC: 264 AN: 68242

European-Finnish (FIN) AF: 0.00205 AC: 73 AN: 35524

Middle Eastern (MID) AF: 0.00332 AC: 14 AN: 4214

European-Non Finnish (NFE) AF: 0.00485 AC: 2920 AN: 602128

Other (OTH) AF: 0.00327 AC: 128 AN: 39194

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000882 AC: 13 AN: 147390 Hom.: 0 Cov.: 0 AF XY: 0.0000838 AC XY: 6 AN XY: 71592

African (AFR) AF: 0.000124 AC: 5 AN: 40320

American (AMR) AF: 0.0000676 AC: 1 AN: 14784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3440

East Asian (EAS) AF: 0.00 AC: 0 AN: 5050

South Asian (SAS) AF: 0.000213 AC: 1 AN: 4688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9104

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.0000898 AC: 6 AN: 66788

Other (OTH) AF: 0.00 AC: 0 AN: 2024

Alfa AF: 0.00542 Hom.: 1380

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Charcot-Marie-Tooth disease type 4 Benign:1

Aug 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.095

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11377100; hg19: chr6-110053824;